Theratechnologies Inc T.TH

RE:RE:RE:RE:RE:RE:RE:RE:Form 10 registration statement just filed

[Wino115]

Thanks for that info. I guess you don't need as much of it, but you have to attach it nonetheless.  I do recall in the Oncology KOL they made it a point to say they now have a lot of inhouse peptide construct skill, so maybe you build a TH19P02 or something. This science is beyond my pay grade, so thanks for putting out the ideas we should address next time we can send in questions. It would be interesting to hear Marsolais's take on your supposition.

jfm1330 wrote: I made a little search about the use of SN38 in Trodelvy. They use more than what I would call a linker to anchor it to the monoclonal antibody. What they use would better be described as a spacer/linker/solubilizer, or a water soluble anchoring arm. This spacer/linker/solubilizer is a big molecule, in fact, it is bigger than SN38 itself. So all that to say that it seems it will not be as easy to use SN38 with TH19P01, than it is with docetaxel. The solubility seems to really be an issue, and on top of it, you still need to come up with a selectively cleavable linker. A linker that will allow stability in the bloodstream, and cleavage inside cancer cells. I am not saying SN38 cannot be used with TH19P01, all I say is that it does not look as easy and I don't know if they will be able to load two molecules of SN38 on the peptide. Also, remember that TH19P01 is much smaller than the monoclonal antibody used in Trodelvy. So it would be impossible to use a very big spacer/linker with it, since the peptide needs to keep its affinity to sortilin. Adding such a big spacer/linker would be very likely to interfere with the affinity of the peptide to sortilin.

https://www.biochempeg.com/article/105.html

https://www.researchgate.net/figure/Representation-of-structure-of-the-CL2A-linker-used-to-bind-SN-38-to-the-anti-TROP-2-IgG_fig3_325940568

jfm1330 wrote: I did not find a direct comparison but my understanding is that SN38 is more potent than docetaxel or doxorubicin. The problem with this molecule is that SN38 is not soluble and stable enough in water and that's why it's not an approved drug by itself. It needs to be linked to another molecule, more soluble in water, with a cleavable link, to be used. It is the case with the approved drug irinotecan, but it is 1000 times less active than SN38 alone. That is why SN38 works in an ADC like Trodelvy, when it is linked to the antibody it is soluble and stable and can enter the cancer cells, than be cleaved.

Thera is hoping they can do something similar by linking it to TH19P01, circumventing the solubility ans stability problems and having a more potent cytotoxic drug that is not under patent. That being said, I don't know if they will be able to load two molecules of SN38 on TH19P01 and keep the solubility of the PDC. SN38 is half the molecular weight of docetaxel, so weight wise and size wise it should work, but it is a less polar molecule than docetaxel that is already not very polar, so solubility of SN38 is lower in water or in serum. Water is polar molecule, and polar molecules are soluble in water. Lipids are non polar molecules, so non polar molecules are soluble in lipids. Let's remember that docetaxel has very low solubility in water, but SN38 is worst. There is also stability problem at physiological pH with SN38. Linking it to another molecule with the right chemical bond, so the right linker, will help stabilizing it. So it seems to be more complcated to work with SN38 than with docetaxel, but it seems to be more potent. 

Another thing about SN38, when compared with docetaxel, is that the rise of the MTD with a SN38-TH19P01 PDC, compared with TH1902  could possibly be much higher since SN38 cannot be used alone and only linked to another molecule in irinotecan that is 1000 times less potent. So if a new PDC using TH19P01 could be a better carrier of SN38 with targeted delivery in cancer cells, my guess is that the MTD of this new PDC in SN38 equivalent could be much higher that the MTD of SN38 through irinotecan. All that to say that they move from doxorubicin to SN38 because they think they can achieve a much more potent PDC than TH1902 or TH1904. Remember, if the proof of concept is established with TH1902, the limiting factor for efficacy will be docetaxel and possible resistance in advanced patients that resist to doceraxel alone.

SPCEO1 wrote: They did mention previously they were moving away from TH-1904 to SN38. Nothing new there but I think it would be interesting to speculate why they have done this. I am not scientifically adept enough to do so myself. They were initially more interested in TH-1904 than 1902. What does SN38 bring to the progress of the Sort1+ program? Is that a natural progression from a science perspective or does it tell us about some potential flaw in 1902?